title: Screening of antibiotics that interact with organic anion-transporting polypeptides 1B1 and 1B3 using fluorescent probes.
abstract: Hepatic organic anion transporters OATP1B1 and OATP1B3 are expressed at the sinusoidal membrane of hepatocytes and contribute to the hepatic uptake of a wide variety of clinically used drugs. To identify the antibiotics that interact with the human organic anion transporters OATP1B1 and OATP1B3, we applied a screening system using fluorescent probes. Twenty-six antibiotics with a variety of mechanisms of action were examined. The screening demonstrated that four antibiotics inhibited OATP1B1-mediated transport and 11 antibiotics inhibited OATP1B3-mediated transport in a concentration-dependent manner. Antibiotics that inhibited OATP1B3-mediated transport tended to exhibit higher affinity than those that inhibited OATP1B1-mediated transport. To clarify whether the antibiotics that interacted with OATP1B1 and/or OATP1B3 were substrates for these transporters, an uptake study was performed. Rifampicin and penicillin were transported by both OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of ceftriaxone, cefmetazole, cefoperazone, and cefotaxime. Macrolides were not significantly transported by either transporter. In conclusion, the results demonstrated that our system is a useful method for the rapid screening of transporter-antibiotic interaction, and we found novel substrates. Our results indicate that OATP1B1 and/or OATP1B3 contribute to the transport process of some antibiotics, and that drug-drug interactions associated with these transporters could occur after the administration of antibiotics.
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980–8574, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Toshiko
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.forename: Minako
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
authors.forename: Junichi
authors.initials: J
authors.lastname: Goto
authors.forename: Takanori
authors.initials: T
authors.lastname: Hishinuma
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D005456:Fluorescent Dyes; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D018942:Macrolides / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D005456:Fluorescent Dyes; D027381:Liver-Specific Organic Anion Transporter 1; D018942:Macrolides; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3